Differentiating the roles of mGlu2 and mGlu3 receptors using LY541850, an mGlu2 agonist/mGlu3 antagonist

Abstract

Despite the potential therapeutic relevance of group II metabotropic glutamate (mGlu) receptors, there has been a lack of pharmacological tools for separating the roles of mGlu2 and mGlu3 receptor subtypes. LY541850 was claimed from human mGlu receptors expressed in non-neuronal cells to be a selective orthosteric mGlu2 agonist and mGlu3 antagonist. We have verified this pharmacological profile of LY541850 in hippocampal slices. Field excitatory post-synaptic potentials (fEPSPs) evoked by stimulation of the temporo-ammonic path (TAP) input to CA1 stratum lacunosum moleculare (SLM) were inhibited by LY541850 in mGlu3−/− mice (EC50 38 nM) and wild-type littermates (EC50 42 nM) to a similar extent but were not significantly affected in mGlu2−/− mice. The group II agonist, DCG-IV, inhibited the fEPSP in all three genotypes. Co-application of DCG-IV and LY541850 in mGlu3−/− and wild-type littermates resulted in an additive effect, whereas in mGlu2−/− mice, LY541850 reversed the inhibitory action of DCG-IV. These results confirm the selective mGlu2 agonist and mGlu3 antagonist actions of LY541850. A similar profile of activity was seen in medial perforant path synapse to the dentate gyrus. Systemic administration of LY541850 to wild-type mice, reduced the increase in locomotor activity following both phencyclidine and amphetamine administration. These data support the hypothesis that mGlu2 receptors mediate the antipsychotic effects of mixed group II agonists.This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.